The experiments described in this proposal are part of a systematic program directed toward the development of biochemical methods by which the status and function of the adrenergic neuron may be determined. Special emphasis is placed on the role of genetic factors in the regulation of adrenergic function. The studies proposed focus on the catecholamine metabolic enzyme catechol-O-methyltransferase (COMT), an enzyme that plays an important role in the metabolism of endogenous catecholamines and of catechol drugs such as L-DOPA, isoproterenol, and alpha-methyldopa. We have already demonstrated the existence of a common genetic polymorphism for COMT activity in the human erythrocyte and the existence of monogenically inherited variants of COMT activity in inbred rats. It is proposed that experiments now be performed to study the role of genetic factors in the regulation of COMT activity in experimental animals and man to determine whether genetically mediated variations in COMT activity result in functional variations in the metabolism of catechol drugs and endogenous catecholamines in vivo. Experiments in inbred rodent strains will evaluate the effects of structural, regulatory, processing, and temporal gene variants in the control of this important enzyme activity. These studies will determine the biochemical basis of genetic variations in enzyme activity, variations in subcellular localization of COMT, ad variations of the response of the enzyme activity to treatment of animals with hormones and drugs. Biochemical studies in man will attempt to determine the biochemical basis of genetically mediated differences in COMT activity in the human erythrocyte and other tissues and to determine whether these genetically determined variations results in significant alterations in catechol metabolism. These experiments represent one step in the development of our ability to characterize individual variations in the status and function of the adrenergic neuron in the intact organism and to understand the biochemical basis of these variations.